Homepage - Conditons outside the liver related to chronic hepatitis C
2014 - Extrahepatic manifestations of chronic hepatitis C virus infection: 297 cases from a tertiary medical center in Beijing, China
View full text here, discussion only with slides is provided below.
Abstract - Healio
Extrahepatic manifestations were common among Chinese patients with chronic hepatitis C virus infection, according to data from a recent study.
Researchers reviewed medical records of 297 patients (mean age, 55 years; 50.8% men) in Beijing with hepatitis C virus (HCV) to determine the presence of clinical manifestations including: fever, fatigue, arthralgia, Raynaud’s phenomenon, palpable purpura, renal impairment, sicca syndrome involving mouth and eyes, thyroid dysfunction, type 2 diabetes mellitus, pulmonary fibrosis, lichen planus, paresthesia, lymphoma and cancers. The mean HCV duration was 14.16 years, and approximately 26% of the cohort had HCV for more than 20 years.
According to results, 62% of patients had at least one extrahepatic manifestation (EM), including fatigue (29.4%), diabetes mellitus (28.2%), renal involvement (12.5%), lymphadenopathy (9.6%), fever (9.4%), thyroid dysfunction (8.1%) and arthralgia (7.4%).
The mean age of patients with EMs (54.9 years vs. 50.2 years; P=.009) was higher than those without EM.
“This study showed that EMs were common in Chinese patients with chronic HCV infection,” the researchers said. “Despite the high prevalence of EMs, only 36% of patients who were anti-HCV positive were seen by a specialist and few were tested for cryoglobulin.
“Therefore, the recognition of EMs [in patients] with chronic HCV infection might deserve more attention in general hospitals in China. Physicians should be aware of the extrahepatic signs and symptoms with chronic HCV infection.”
Disclosure: Relevant financial disclosures were not provided by researchers.
Chronic HCV infection can be easily overlooked due to its insidious onset and nonspecific clinical manifestations. As shown in this study, presentation with EMs is common among Chinese patients with CHC. Clinical vigilance is critical for a timely diagnosis. Our study showed that 62.0% of the patients presented at least one EM. This result is similar to those reported from a large prospective study,3in which 74% of 1 614 patients with chronic HCV infection had at least one EM. Fatigue was the most common nonspecific symptom in chronic HCV infection, present in 29.4% of patients included in this study. Studies have suggested an association between fatigue and HCV-related cryglobulinemia.4
High prevalence of glucose metabolic disorders has been well documented in patients with chronic HCV infection, including insulin resistance (32%–70%), type 2 diabetes mellitus (14%–50%), and metabolic syndrome (26%–51%). In our study, type 2 diabetes mellitus was diagnosed in 79 of 280 patients (28.2%), which is a higher prevalence than that of the general population. The mean level of fasting blood glucose is (8.52±2.90) mmol/L, 2-hour postprandial blood glucose is (15.16±7.04) mmol/L, and glycosylated hemoglobin is 8.07%±2.07%. This finding is consistent with the study by Liu et al,5which reported a higher prevalence of type 2 diabetes mellitus in 155 HCV patients (19.35%) compared with that of controls (7.55%).
A prospective cohort of Taiwanese patients found HCV infection an independent predictor of diabetes, especially for people who are younger, with a higher body mass index, or HBV coinfection.6Study showed that treatment with interferon plus ribavirin reduced the risk of glucose metabolic disorders in patients with chronic HCV infection.7In addition, insulin resistance or risk factors of diabetes in the CHC patients might reduce the effectiveness of antiviral therapy and the rate of sustained virological response (SVR).8,9
Some may speculate that improving insulin resistance through exercise, weight loss, and the use of insulin- sensitizing agents might improve SVR rates. GN, speciﬁcally type I MPGN is often associated with type II cryoglobulinemia in patients with chronic HCV infection. Patients may present with proteinuria, edema, hypertension, and hypocomplementemia.
Misiani et al10found a high prevalence of HCV antibodies (66%) and HCV RNA (81%) in patients with cryoglobulinemic GN. In previous studies, renal disease was diagnosed in 20%–30% of cryoglobulin-positive patients with HCV infection.11In the present study, MPGN seems not an overwhelming majority; the prevalence of mesangial proliferative GN seemed similar to MPGN. It might be the racial difference or limited sample size. Although the mechanisms that cause renal damage are not fully elucidated, risk factors for the development of severe renal failure include age, serum creatinine level, and proteinuria at the onset of renal disease.12
MC vasculitis was a well-studied manifestation of HCV infection, and its subclinical form has been reported in 19%–50% of the patients besides Mediterranean.13A meta-analysis showed that 44% patients with chronic HCV infection had circulating immune complexes with cryoprecipitating properties.14In our study, cryoglobulins were positive in 4 of 11 patients tested (36.4%). A study suggested that HCV infection was associated with type II MC, with clinical features of vasculitis which affect the small-sized blood vessels of the skin, joints, nerves, and kidneys.15
Clinical studies suggest that lichen planus, mainly the oral form, is associated with HCV infection.16Gandolfoet al16found serum anti-HCV antibodies in 28 (62%) and serum HCV RNA in 27 (60%) of 45 Japanese patients with oral lichen planus. However, it has not been confirmed by other reports.17In our study, oral lichen planus was diagnosed in one patient and skin lesion in one patient. An association between lymphomas and HCV infection has been reported.
A high prevalence of HCV seropositivity (15%) was reported from patients with lymphoproliferative disorders, particularly those with B-cell non-Hodgkin lymphoma NHL.18In a meta-analysis including 5542 NHL patients, 13% had HCV infection, with an even higher prevalence in patients from Japan (17%) and Italy (20%).19 About 10% patients with HCV-related MC eventually developed lymphoma.20In the present study, eight patients (2.7%) were diagnosed with lymphoma.
A recent study in Poland showed that several factors were associated with the presence of EMs in HCV patients, including older age, long duration of HCV infection, higheraspartateaminotransferaseand gamma-glutamyl transpeptidase levels, lower platelet count, higher inflammatory activity, and advanced liver fibrosis. However, only lower platelet count remained significant in multivariate analyses.21In our study, the mean age of patients with EM was older compared with those without EM. Since previous study showed that the elderly patients had lower SVR than nonelderly patients during pegylated interferon-alpha-2a plus ribavirin combination therapy,22more research is needed to investigate whether the lower SVR is related to the existence of EM in elderly CHC patients.
Because HCV genotype was tested in only a few patients, we could not assess the association between HCV genotype and EM. In conclusion, this study showed that EMs were common in Chinese patients with chronic HCV infection, particularly fatigue, type 2 diabetes, renal impairment, lymphadenophy, fever, and thyroid dysfunction. Despite the high prevalence of EM, only 36.2% (194/536) patients with anti-HCV positive were seen by a specialist and a few were tested for cryoglobulin. Therefore, the recognition of the EM with chronic HCV infection might deserve more attention in general hospitals in China.
Physicians should be aware of the extrahepatic signs and symptoms with chronic HCV infection. Prospective study is needed to investigate the incidence and risk factors of extrahepatic disorders of chronic hepatic C in Chinese population. Acknowledgments:We thank all healthcare providers who had participated in taking care of our patients. We are grateful to all the medical record staff for their support. We thank Han Yang and Zhang Yueqiu for supporting data collection.
- 1.Hadziyannis SJ. The spectrum of extrahepatic manifestations in hepatitis C virus infection. J Viral Hepat 1997; 4: 9-28.
- 2.Manns MP, Rambusch EG. Autoimmunity and extrahepatic manifestations in hepatitis C virus infection. J Hepatol 1999; 31: 39-42.
- 3.Cacoub P, Poynard T, Ghillani P, Charlotte F, Olivi M, Piette J C, et al. Extrahepatic manifestations of chronic hepatitis C. multivirc group. Multidepartment virus C. Arthritis Rheum 1999; 42: 2204-2212.
- 4.Diana VS, Anelia HT, Elisaveta JN, Anastasia PM, Evgenii AH, Rumiana PD, et al. Chronic hepatitis C virus infection: prevalence of extrahepatic manifestations and associated with cryoglobulinemia in Bulgarian patients. World J Gastroenterol 2007; 13: 6518-6528.
- 5.Liu SQ, Dong MG, Men CH, Yang MJ, Liu W. Relation research between chronic hepatitis C and type 2 diabetes (in Chinese). J Pract Diagn Ther 2011; 25: 83-84.
- 6.Wang CS, Wang ST, Yao WJ, Chang TT, Chou P.Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol 2007; 166: 196-203.
- 7.Romero-Gomez M, Fernandez-Rodriguez CM, Andrade RJ, Diago M, Alonso S, Planas R,et al.Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol 2008; 48: 721-727.
- 8.Poustchi H, Negro F, Hui J, Cua IH, Brandt LR, Kench JG,et al. Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3. J Hepatol 2008; 48: 28-34.
- 9.Romero-Gómez M, Del MV, Andrade RJ, Salmerón J, Diago M, Fernández-Rodríguez CM, et al. Insulin resistance impairs sustained response rate to peginterferon plusribavirin in chronic hepatitis C patients. Gastroenterology 2005; 128: 636-641.
- 10.Misiani R, Bellavita P, Fenili D, Borelli G, Marchesi D, Massazza M, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 1992; 117: 573-577.
- 11.Daghestani L, Pomeroy C. Renal manifestations of hepatitis C infection. Am J Med 1999; 106: 347-354.
- 12.Roccatello D, Fornasieri A, Giachino O, Rossi D, Beltrame A, Banfi G, et al. Multicenter study on hepatitis C virus-related cryoglobulinemic glomerulo-nephritis. Am J Kidney Dis 2007; 49: 69-82.
- 13.Puchner KP, Berg T. Extrahepatic manifestations of chronic HCV. Z Gastroenterol 2009; 47: 446-456.
- 14.Kayali Z, Buckwold VE, Zimmerman B, Schmidt WN. Hepatitis C, cryoglobulin-emia, and cirrhosis: a meta-analysis. Hepatology 2002; 36: 978-985.
- 15.Zignego AL, Giannini C, Ferri C. Hepatitis C virus-related lymphoproliferative disorders: an overview. World J Gastroenterol 2007; 13: 2467-2478.
- 16.Gandolfo S, Carrozzo M. Lichen planus and hepatitis C virus infection. Minerva Gastroenterol Dietol 2002; 48: 89.
- 17.Tucker SC, Coulson IH. Lichen planus is not associated with hepatitis C virus infection in patients from north West England. Acta Derm Venereol 1999; 79: 378-379.
- 18.Saadoun D, Bieche I, Maisonobe T, Asselah T, Laurendeau I, Piette JC, et al. Involvement of chemokines and type 1 cytokines in the pathogenesis of hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy. Arthritis Rheum 2005; 52: 2917-2925.
- 19.Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in B cell non-Hodgkin’s lymphoma: systematic review and meta-analysis. Gastroenterology 2003; 125: 1723-1732.
- 20.Ghinoi A, Mascia MT, Puccini R, Ferri C. Autoimmune and lymphoproliferative HCV-correlated manifestations: example of mixed cryoglobulinaemia (review). G Ital Nefrol 2004; 21: 225-237.
- 21.Zarebska-Michaluk DA, Lebensztejn DM, Kryczka WM, Skiba E. Extrahepatic manifestations associated with chronic hepatitis C infections in Poland. Adv Med Sci 2010; 55: 67-73.
- 22.Zheng YY, Fan XH, Wang LF, Tian D, Huo N, Lu HY, et al. Efficacy of pegylated interferon-alpha-2a plus ribavirin for patients aged at least 60 years with chronic hepatitis C. Chin Med J 2012; 125: 1852-1856.